Project Summary LTE4 is the stable cysteinyl leukotriene (cysLT), detected in the biologic fluids of patients with asthma triggered by allergen challenge, aspirin, and respiratory viruses. LTE4 elicits cutaneous edema in normal controls and elicits both airflow obstruction and basophil and eosinophil recruitment to the lung in patients with asthma. Our group recently identified GPR99 as the high affinity receptor for LTE4 and demonstrated that it mediates LTE4-elicited cutaneous edema in mice lacking the conventional cysLT receptors, CysLT1R and CysLT2R. However, the mechanism(s) by which LTE4 induces lung pathobiology remains poorly understood and the role of GPR99 has not been elucidated. We have found that GPR99 is expressed on both murine and human respiratory epithelial cells (EpCs) and controls both their activation and development. As GPR99 is resistant to currently available cysLT receptor inhibitors, the findings from this proposal will determine whether GPR99 is a logical therapeutic target to reduce mucus production, airflow obstruction, or type 2 inflammation in asthma. In Aim 1 we will define the cellular and transcriptional mechanisms by which GPR99 regulates murine lung EpC development. In Aim 2, we will use RNAseq and an in vitro culture system to determine the extent to which GPR99 regulates human airway EpC differentiation and explore the pathways through which this occurs. In Aim 3, we will identify the contribution of the cysLT/GPR99 axis to several models of type 2 pulmonary inflammation and determine how the EpC actions of GPR99 might control this process.